Leukemia, Myeloid study with Targeted-Capture data on dbGaP (254 participants)

phs003303 — Molecular and Clinical Analyses of PHF6 Mutant Myeloid Neoplasia Provide    Clues as to Their Pathogenesis and Therapeutic Targeting

<a href="https://www.ncbi.nlm.nih.gov/gene/84295">PHF6</a><a href="https://www.ncbi.nlm.nih.gov/gene/84295"> </a>mutations (PHF6MT) are identified in various myeloid neoplasms (MN). However, little is known about the precise function and consequences of PHF6 in MN. Our comprehensive genomic analyses yielded three main findings. Firstly, we revealed a different pattern of genes correlating with PHF6MT in male and female cases. When analyzing male and female cases separately, in only male cases, <a href="https://www.ncbi.nlm.nih.gov/gene/861">RUNX1</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/7307">U2AF1</a> were co-mutated with PHF6. In contrast, female cases revealed co-occurrence of <a href="https://www.ncbi.nlm.nih.gov/gene/171023">ASXL1</a> mutations and X-chromosome deletions with PHF6MT. Next, proteomics analysis revealed a direct interaction between PHF6 and the pioneer transcription factor RUNX1. Both proteins co-localize in active enhancer regions that define the context of lineage differentiation. Finally, we demonstrated a negative prognostic role of PHF6MT, especially in association with RUNX1. The negative effects on survival were additive as PHF6MT cases with RUNX1 mutations had worse outcomes when compared to cases carrying single mutation or wild-type.